Does Breast Cancer That Seems to Have High Recurrence Risk Always Need Chemo?

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Welcome to the Breastcancer.org Podcast, the podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here’s your host, Breastcancer.org Senior Editor, Jamie DePolo.

Jamie DePolo: Hello, I'm Jamie DePolo, senior editor at Breastcancer.org. I'm podcasting live from the 2026 American Society of Clinical Oncology Annual Meeting.

At the meeting, the results of the OPTIMA Trial were presented, and they suggest that some people diagnosed with early-stage hormone receptor-positive, HER2-negative breast cancer with a low Prosigna risk of recurrence score can safely skip chemotherapy and only take hormonal therapy after surgery.

I'm joined by Dr. Iain MacPherson, professor of breast oncology at the University of Glasgow, who was chief investigator of this study. Dr. MacPherson, welcome to the podcast.

Dr. Iain MacPherson: Hi, Jamie. It’s a pleasure to be with you today. Thank you.

Jamie DePolo: Thanks for joining us.

So, to start, could you tell us a little bit about the Prosigna test? What does it do? My understanding is that it helps predict the risk of distant recurrence, also called metastatic recurrence. Does it also give people a risk of local recurrence? The breast cancer coming back in the same breast or opposite breast, something like that?

Dr. Iain MacPherson: Yes. So, the Prosigna test is a test which is performed on breast cancer tissue that’s been removed during a patient’s operation. So that can then be sent away, the test can be performed. It’s based on, really, the level of activity of 50 genes within that particular cancer. And the key readout from the Prosigna test is a thing called risk of recurrence score, and actually that’s based around the risk of that patient going on to develop a distant or metastatic recurrence in 10 years’ time.

In OPTIMA we've done something slightly different. What we’ve been interested in is whether the risk of recurrence score might also predict how sensitive or insensitive a cancer is to chemotherapy.

Jamie DePolo: Okay. Perfect. So, you talked about the OPTIMA trial. You are the chief investigator. Could you summarize it for us, as well as the results?

Dr. Iain MacPherson: Yes. So, OPTIMA, I think, is really a landmark clinical trial in early breast cancer. And the reason is, it addresses a question that oncologists and patients for many years have been struggling with, and that is exactly which patients with clinically high-risk breast cancer really benefit from chemotherapy and can we identify those patients who could safely avoid it?

So OPTIMA was an international phase III randomized clinical trial. We recruited over 4,400 patients, all of whom had the estrogen receptor-positive or hormone receptor-positive, HER2-negative subtype of breast cancer and following surgical removal of their tumor. And these were all patients who ordinarily would receive a course of adjuvant or preventative chemotherapy followed then by a prolonged course of hormonal treatment.

Now, within the clinical trial, patients who volunteered to take part were allocated to one of two groups. So, half the patients were allocated to what we would call the control group and they received standard treatment. So that was a course of chemotherapy followed by standard endocrine therapy. But the other half of patients were in the test-directed group, and these patients had the Prosigna test performed and then their treatment was decided according to the result of the Prosigna test. So patients with a high Prosigna score still went onto receive standard treatment: chemotherapy followed by hormonal treatment. But patients whose cancers had a low Prosigna score they avoided chemotherapy and went straight onto endocrine therapy.

Jamie DePolo: And then, for the results, you compared, was it…I want to make sure I get this right. It was anybody who had a recurrence you looked at who did and who didn’t, is that…am I understanding that correctly?

Dr. Iain MacPherson: Yes. So, that’s exactly right. So, what we were interested in then doing was following up these patients and understanding using an arbitrary timepoint of five years, what had happened to those patients? How many of them were alive and well without a recurrence of their breast cancer at five years? And I mean really the key results of OPTIMA are firstly that two-thirds of patients in whom we performed the Prosigna test, their cancers did have a low score. So, two-thirds of patients who would usually have received chemotherapy avoided it.

We compared that group to those patients also with low score cancers, but in the control group, so who all received chemotherapy. And the results at five years were very, very similar. So, around 94% of patients in both groups, whether or not they had chemotherapy remained alive and free of their breast cancer.

Jamie DePolo: Which is great. I'm wondering. Did you break any of the results out by the number of positive nodes? Because it was interesting to me that people could have up to nine positive lymph nodes, which seems a little high, and I understand that gives them a higher risk of recurrence just clinically. But did anybody with nine…with that many positive nodes have a low Prosigna risk of recurrence score? And did you, like, separate those people out at all?

Dr. Iain MacPherson: So, that’s a great question. And one of the unique features of OPTIMA was that we did recruit patients with up to nine involved nodes. And the reason is, in OPTIMA we’re using the Prosigna really to interrogate the cancer’s biology, the fundamental biology of the cancer, whether or not that cancer is likely to be sensitive to chemotherapy. And we thought that would be the same regardless of the number of nodes. But of course, we need to generate robust, high-level evidence, you know, to prove that.

So, we did recruit patients with up to nine involved nodes. About 20%, one in five patients entering the trial had between four and nine involved nodes. And that’s important because there have been some previous trials with tests similar to Prosigna, but they’ve been limited to patients with one to three involved nodes. So we then got into this higher risk group, at least based on clinical factors. And so, we looked very carefully within that group of patients with four to nine involved nodes, and we found that the overall result applied equally to that group. 

So actually, the biology is more important than the number of nodes. There is still essentially no difference between patients with four to nine nodes whether or not they had chemotherapy if their cancer had a low Prosigna risk ofrRecurrence score.

Jamie DePolo: Okay. And then, the other thing I'm curious about, chemotherapy suppresses ovarian function. The pre-menopausal women in the study if they had the Prosigna test, had a low risk of recurrence score, and were assigned a hormonal therapy only, they also got ovarian suppression. So, I'm wondering…and I know a question has been amongst the oncology community, how much does ovarian suppression contribute to positive outcomes and how much does chemotherapy? And I know the study wasn’t designed to do that, but does it give us any insight into that at all?

Dr. Iain MacPherson: Yes, absolutely. So, that’s the other unique feature of OPTIMA. So, we do have some previous clinical trials in this space and actually they’ve given very mixed results in pre-menopausal patients. And you know, currently this type of test is not recommended in pre-menopausal women really at higher risk of recurrence. For example, because of involved axillary nodes. And that’s because the previous trials have really shown very mixed performance of tests in this space. And oncologists have been scratching their heads as to why that is.

There are two possible explanations to that. One is that cancer biology is genuinely different in pre-menopausal women and a low risk of recurrence score means a different thing. That’s one possible explanation. The other explanation is that chemotherapy can at least temporarily in most pre-menopausal suppress ovarian function. And we know, in fact, ovarian function suppression is an important part of hormonal treatment for pre-menopausal women.

These older trials that are mentioned didn’t really control for that. So, they were comparing, in patients with low scores, chemotherapy, plus chemotherapy-induced ovarian function suppression, plus tamoxifen, see, versus tamoxifen. We haven’t known if it was the chemotherapy directly or the chemotherapy-induced ovarian function suppression that’s important, and explains why we had these discordant results. So, in OPTIMA from the outset all patients volunteering to take part as part of their endocrine therapy received ovarian suppression in all arms of the trial. And so that removes that confounding and then we’re purely looking at the direct effect of the chemotherapy. And I think that’s why in OPTIMA that in low-score tumors we’re not seeing that benefit.

But the important thing to consider is that all patients received ovarian function suppression. So, if we’re going to avoid chemotherapy in a pre-menopausal patient, based on these results, that would be in the proviso that their endocrine treatment would include ovarian function suppression.

Jamie DePolo: And then, I'm also wondering…this was hormone receptor-positive disease and the follow up was five years. I've read some studies showing that hormone receptor-positive disease can come back later, like 10, 15, even 20 I think one study said. So, are you planning to follow this group longer or is this enough? Help me understand that.

Dr. Iain MacPherson: Yeah. I mean, so absolutely one of the things about hormonal breast cancer is there’s really kind of a prolonged risk of relapse at later times. Now, chemotherapy we know is effective at reducing the risk of recurrence, particularly over the first five years. It doesn’t really impact on these late recurrences in the same way. So actually with the follow up in our trial in looking at that five-year endpoint, that is really sufficient to determine whether or not chemotherapy would have an effect here.

But to come back to your question, yes, we’re absolutely going to follow up this patient population for…well, certainly for 10 years anyway. We wouldn’t expect that really to change the results that we’ve reported today. Some of our estimates might get a little bit more precise with some additional follow up, but I think the detail that we presented today have had enough follow up for us to make that conclusion about whether or no chemotherapy would impact on the risk of recurrence.

Jamie DePolo: Okay. Thank you. And then, I just have a couple more questions. So, Prosigna, as you said, you explained, is giving a risk of recurrent score of distant or metastatic recurrence. And I want to make sure I'm understanding this study right because it sounded like when you were looking at breast cancer…invasive breast cancer-free survival it could’ve been local or distant. So would this be sort of a change in the way the Prosigna test is used?

Dr. Iain MacPherson: I mean, I think this would be a change in the way the Prosigna test is used, in particular extending it into this group of patients with higher degrees of lymph node involvement and also into pre-menopausal patients.

The trial, like many trials, we use an endpoint, which is made up of a mixture of different things that may or may not happen, and that does include local recurrence of breast cancer, distant recurrence of breast cancer, if a patient was unfortunately to die for any reason. That’s actually included within that endpoint as well.

When we look at our trial data, most of the things that happened that contributed to our statistical analysis were in fact distant recurrences of breast cancer and that’s usually what we would expect. Local recurrences are actually less common now due to a whole host of reasons, so primarily distant recurrences. But the endpoint we report, invasive breast cancer-free survival, it’s a mixture of different things.

Jamie DePolo: Okay. Thank you. And then, finally, last question. I know there were some men in this study. It wasn’t a large number. Do you think the results apply to men with breast cancer as well or were there not enough men in the study?

Dr. Iain MacPherson: So, we were very keen to include men in this study, because, you know, that male breast cancer unfortunately is often an underrepresented, under-researched area. So, this trial was open to men with breast cancer. About 1% of our patients were male and that’s in line, perhaps even slightly more than we would have expected. It does make it a little bit difficult because these are small numbers.

On the other hand, we do know from previously published data that the Prosigna test does seem to perform very similarly in men as in women. So there’s no particular reason to think that the results should be different. And I think this is, you know, part of shared decision-making and informed consultations with our patients. So the numbers are small, but I think with these caveats these are certainly results I would discuss with a male patient for example.

Jamie DePolo: Perfect. Dr. MacPherson, thank you so much. I appreciate your time and helping us understand this important study.

Dr. Iain MacPherson: Thank you very much for having me. It’s a pleasure.

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